The present invention relates to a topical pharmaceutical composition, formulated with at least one local anesthetic and at least one opioid analgesic, and to methods of providing pain relief to a subject through topical administration of the composition in an amount and a duration sufficient to synergistically potentiate an antinociceptive response.
Many chemical and pharmaceutical compositions are known to produce antinociceptive effects. These include, for instance, steroids; non-steroidal anti-inflammatory drugs; local anesthetics; and opioids. These antinociceptive drug classes are useful for modulating many different types of pain, including postoperative, acute, chronic and inflammatory pain. Pain can be alleviated systemically for instance by ingestion or parenteral administration of a suitable composition or, at the site of the pain for instance, by local or topical administration thereof.
Opiates are drugs derived from opium and include morphine, codeine and a wide variety of semisynthetic opioid congeners derived from these and from thebaine, another component of opium. Opioids include the opiates and all agonists and antagonists with morphine-like activity and naturally occurring endogenous and synthetic opioid peptides. Although morphine and other morphine-like opioid agonists are commonly used to produce analgesia, the severity and high incidence of side effects limits their use.
There are now many compounds with pharmacological properties similar to those produced by morphine, but none has proven to be clinically superior in relieving pain. References to morphine herein will be understood to include morphine-like agonists as well. The effects of morphine on human beings are relatively diverse and include analgesia, drowsiness, mood changes, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and alterations of the endocrine and autonomic nervous systems. Pasternak (1993) Clin. Neuropharmacol. 16:1. Doses of morphine need to be tailored based on individual sensitivity to the drug and the pain-sparing needs of the individual. For instance, the typical initial dose of morphine (10 mg/70 kg) relieves postoperative pain satisfactorily in only two-thirds of patients. Likewise, responses of an individual patient can vary dramatically with different morphine-like drugs and patients can have side effects with one such drug and not another. For example, it is known that some patients who are unable to tolerate morphine may have no problems with an equianalgesic dose of methadone. The mechanisms underlying individual variations in response to morphine and morphine-like agonists have not been defined.
The analgesic effects of morphine are transduced through opioid receptors in the central nervous system (CNS), located at both spinal and multiple supraspinal sites. Morphine and its agonists induce profound analgesia when administered intrathecally or instilled locally into the dorsal horn of the spinal cord. Recently, it has been shown that opioids elicit analgesia at peripheral sites and therefore, topical administration of morphine is also effective in modulating pain. Several mechanisms of action are believed to mediate the inhibition of nociceptive reflexes from reaching higher centers of the brain, including the inhibition of neurotransmitter release by opioid receptors on the termini of primary afferent nerves and post-synaptic inhibitory actions on intemeurons and on the out-put neurons of the spinothalamic tract.
The instillation of morphine into the third ventricle or within various sites in the midbrain and medulla, most notably the periaqueductal gray matter, the nucleus raphe magnus, and the locus ceruleus results in profound analgesia. Although the neuronal circuitry responsible has not been defined, this produces enhanced activity in the descending aminergic bulbospinal pathways that exert inhibitory effects on the processing of nociceptive information in the spinal cord. Simultaneous administration of morphine at both spinal and supraspinal sites results in a synergized analgesic response, with a ten-fold reduction in the total dose of morphine necessary to produce equivalent analgesia at either site alone.
Morphine also exerts effects on the neuroendocrine system. Morphine acts in the hypothalamus to inhibit the release of gonadotropin releasing hormone (GnRH) and corticotropin-releasing factor (CRF), thus decreasing circulating concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), adrenocorticotropin (ACTH), and xcex2-endorphin. As a result of the decreased concentrations of pituitary trophic hormones, the plasma concentrations of testosterone and cortisol decline. The administration of opiates increases the concentration of prolactin (PRL) in plasma, most likely by reducing the dopaminergic inhibition of PRL secretion. With chronic administration, tolerance eventually develops to the effects of morphine on hypothalamic releasing factors.
Opiates can interfere with normal gastrointestinal functioning. Morphine decreases both gastric motility and stomach secretion of hydrochloric acid. Morphine can delay passage of gastric contents through the duodenum for as long as 12 hours. Morphine also decreases biliary, pancreatic, and intestinal secretions and delays the digestion of food in the small intestine.
Propulsive peristaltic waves in the colon are diminished or abolished after administration of morphine and commonly, constipation occurs. For a detailed review of the physiologic effects of morphine, see Reisine and Pasternak (1996) Goodman and Gilman""s, The pharmacological basis of therapeutics, Ninth Edition (Hardman et al. eds.) McGraw-Hill pp. 521-555.
Morphine also exerts effects on the immune system. The most firmly established immunologic effect of morphine is its ability to inhibit the formation of human lymphocyte rosettes. The administration of morphine to animals causes suppression of the cytotoxic activity of natural killer cells and enhances the growth of implanted tumors. These effects appear to be mediated by actions within the CNS. By contrast, xcex2-endorphin enhances the cytotoxic activity of human monocytes in vitro and increases the recruitment of precursor cells into the killer cell population; this peptide also can exert a potent chemotactic effect on these cells. A novel type of receptor (designated "Egr") may be involved. These effects, combined with the synthesis of proopiomelanocortin (POMC) and preproenkephalin by various cells of the immune system, have stimulated studies of the potential role of opioids in immune function regulation. Sibinga et al. (1988) Annu. Rev. Immunol. 6:219.
Side effects resulting from the use of morphine range from mild to life-threatening. Morphine causes constriction of the pupil by an excitatory action on the parasympathetic nerve innervating the pupil. Morphine depresses the cough reflex through inhibitory effects on the cough centers in the medulla. Nausea and vomiting occur in some individuals through direct stimulation of the chemoreceptor trigger zone for emesis, in the postrema of the medulla. Therapeutic doses of morphine also result in peripheral vasodilatation, reduced peripheral resistance and inhibition of baroreceptor reflexes in the cardiovascular system.
Additionally, morphine provokes the release of histamines, which can cause hypotension. Morphine depresses respiration, at least in part by direct effects on brainstem regulatory systems. In humans, death from morphine poisoning is nearly always due to respiratory arrest. Opioid antagonists can produce a dramatic reversal of severe respiratory depression; naloxone is currently the treatment of choice. High doses of morphine and related opioids can produce convulsions that are not always relieved by naloxone.
The development of tolerance and physical dependence with repeated use is a characteristic feature of all opiates. Dependence seems to be closely related to tolerance, since treatments that block tolerance to morphine also block dependence. In vivo studies in animal models demonstrate the importance of neurotransmitters and their interactions with opioid pathways in the development of tolerance to morphine. Blockade of glutamate actions by noncompetitive and competitive NMDA (N-methyl-D-aspartate) antagonists blocks morphine tolerance. Trujillo and Akil (1991) Science 251:85; Elliott et al. (1994) Pain 56:69; U.S. Pat. Nos. 5,654,281; 5,523,323; and 5,321,012; and WO/98/14427. NMDA antagonists include, but are not limited to, dextromethorphan, dextrorphan, ketamine, pyroloquinoline quinone, cis-4-(phosphonomethyl)-2-piperdine carboxylic acid, and MK801. Blockade of the glycine regulatory site on NMDA receptors exerts similar effects to block tolerance. Kolesnikov et al. (1994) Life Sci. 55:1393. Administering inhibitors of nitric oxide synthase in morphine-tolerant animals reverses tolerance, despite continued opioid administration. Kolesnikov et al. (1993) Proc. Natl. Acad. Sci. USA 90:5162.
These studies illustrate several important aspects of tolerance and dependence. First, the selective actions of drugs on tolerance and dependence demonstrate that analgesia can be dissociated from these two unwanted actions. Second, the reversal of preexisting tolerance by NMDA antagonists and nitric oxide synthase inhibitors indicates that tolerance is a balance between activation of processes and reversal of those processes. These observations suggest that, by use of selective agonists and/or antagonists, tolerance and dependence in the clinical management of pain can be minimized or disassociated from the therapeutic effects. Unfortunately, NMDA antagonists are difficult to administer systemically due to their profound psychomimetic and dysphoric actions.
In addition to morphine, a variety of opioids are suitable for clinical use. These include, but are not limited to, Levorphanol, Meperidine, Fentanyl, Methadone, Codeine, Propoxyphene and various opioid peptides. Certain opioids are mixed agonists/antagonists and partial agonists. These include pentazocine, nalbuphine, butorphanol, and buprenorphine.
The pharmacological effects of levorphanol closely parallel those of morphine although clinical reports suggest that levorphanol produces less nausea. Dextromethorphan, the d-isomer of the codine analog of levorphanol, has been used specifically for the treatment of mouth pain. See, U.S. Pat. No. 4,446,140.
Meperidine exerts its chief pharmacological effects on the CNS and the neural elements in the bowel. Meperidine produces a pattern of effects similar, but not identical to, those described for morphine. In equianalgesic doses, meperidine produces as much sedation, respiratory depression, and euphoria as morphine. The pattern of unwanted side effects that follows the use of meperidine are similar to those observed after equianalgesic doses of morphine, except that constipation and urinary retention are less common.
Fentanyl is a synthetic opioid estimated to be 80 times as potent as morphine as an analgesic. High doses of fentanyl can result in severe toxicity and produce side effects including muscular rigidity and respiratory depression.
Methadone is an opioid with pharmacologic properties similar to morphine. The pharmacologic properties of methadone include effective analgesic activity, efficacy by the oral route and persistent effects with repeated administration. Side effects include detection of miotic and respiratory-depressant effects for more than 24 hours after a single dose, and, marked sedation is seen in some patients. Effects on cough, bowel motility, biliary tone and the secretion of pituitary hormones are qualitatively similar to those of morphine. In contrast to morphine, codeine is approximately 60% as effective orally as parenterally, both as an analgesic and as a respiratory depressant.
Codeine has an exceptionally low affinity for opioid receptors, the analgesic effect of codeine is due to its conversion to morphine. However, codeine""s antitussive actions probably involve distinct receptors that specifically bind codeine.
Propoxyphene produces analgesia and other CNS effects that are similar to morphine. It is likely that at equianalgesic doses the incidence of side effects such as nausea, anorexia, constipation, abdominal pain, and drowsiness would be similar to those of codeine.
Opioid antagonists have therapeutic utility in the treatment of overdosage with opioids. As understanding of the role of endogenous opioid systems in pathophysiologic states increases, additional therapeutic indications for these antagonists will emerge. If endogenous opioid systems have not been activated, the pharmacologic actions of opioid antagonists depend on whether or not an opioid agonist has been administered previously, the pharmacologic profile of that opioid and the degree to which physical dependence on an opioid has developed. The antagonist naloxone produces no discernible subjective effects aside from slight drowsiness. Naltrexone functions similarly, but with higher oral efficacy and a longer duration of action. Currently, naloxone and naltrexone are used clinically to treat opioid overdoses. Their potential utility in the treatment of shock, stroke, spinal cord and brain trauma, and other disorders that can involve mobilization of endogenous opioids remains to be established.
The complex interactions of morphine and drugs with mixed agonist/antagonist properties are mediated by multiple classes of opioid receptors. Opioid receptors comprise a family of cell surface proteins, which control a range of biological responses, including pain perception, modulation of affective behavior and motor control, autonomic nervous system regulation and neuroendocrinologic function. There are three major classes of opioid receptors in the CNS, designated mu, kappa and delta, which differ in their affinity for various opioid ligands and in their cellular distribution. The different classes of opioid receptors are believed to serve different physiologic functions. Olson et al. (1989) Peptides 10:1253; Lutz and Pfister (1992) J. Receptor Res. 12:267; and Simon (1991) Medicinal Res. Rev. 11:357. Morphine produces analgesia primarily through the mu-opioid receptor. However, among the opioid receptors, there is substantial overlap of function as well as of cellular distribution.
The mu-opioid receptor mediates the actions of morphine and morphine-like opioids, including most clinical analgesics. In addition to morphine, several highly selective agonists have been developed for mu-opioid receptors, including [D-Ala2,MePhe4,Gly(ol)5]enkephalin (DAMGO), levorphanol, etorphine, fentanyl, sufentanil, bremazocine and methadone. Mu-opioid receptor antagonists include naloxone, naltrexone, D-Phe-Cys-Try-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), diprenorphine, xcex2-funaltrexamine, naloxonazine, nalorphine, nalbuphine, and naloxone benzoylhydrazone. Differential sensitivity to antagonists, such as naloxonazine, indicates the pharmacologic distinctions between the mu-opioid receptor subtypes, mu1 and mu2. Several of the opioid peptides also interact with mu-opioid receptors.
There are three known kappa-opioid receptor subtypes, designated kappa1, kappa2 and kappa3. Each kappa-opioid receptor subtype possesses distinct pharmacologic properties. For example, kappa1-opioid receptors produce analgesia spinally and kappa3-opioid receptors relieve pain through supraspinal mechanisms. In addition, the kappa1-opioid receptor selectively binds to the agonist U50,488. Additional agonists of the kappa1-opioid receptor include etorphine; sufentanil; butorphanol; xcex2-funaltrexamine; nalphorine; pentazocine; nalbuphine; bremazocine; ethylketocyclazocine; U50,488; U69,593; spiradoline; and nor-binaltorphimine. Agonists of the kappa3-opioid receptor include etorphine; levorphanol; DAMGO; nalphorine; nalbuphine; naloxone benzoylhydrazone; bremazocine; and ethylketocyclazocine. Effects of agonists on the kappa1-opioid receptors are reversed by a number of antagonists, including buprenorphine, naloxone, naltrexone, diprenorphine, naloxonazine, naloxone benzoylhydrazone, naltrindole and nor-binaltorphimine. Antagonists of the kappa3-opioid receptors include naloxone, naltrexone and diprenorphine.
The delta-opioid receptors are divided into two subclasses, delta1 and delta2. The delta opioid receptors modulate analgesia through both spinal and supraspinal pathways. The two subclasses were proposed based on their differential sensitivity to blockade by several novel antagonists. Portoghese et al. (1992) Eur. J. Pharmacol. 218:195; and Sofuoglu et al. (1991) J. Pharmacol. Ther. 257:676. The agonists [D-Pro2,Glu4]deltorphin and [D-Ser2,Leu5]enkephalin-Thr6 (DSLET) preferentially bind to the delta2 receptors, whereas [D-Pen2,D-Pen5]enkephalin (DPDPE) has a higher affinity for delta1 receptors.
There are three distinct families of endogenous opioid peptides, the enkephalins, endorphins and dynorphins. Each such peptide is derived from a distinct precursor polypeptide. Mu-opioid receptors have a high affinity for the enkephalins as well as xcex2-endorphin and dynorphin A. The enkephalins are also endogenous ligands for the delta receptors, along with dynorphin A and dynorphin B. The kappa1-opioid receptor endogenous opioid peptide agonists include dynorphin A, dynorphin B and xcex1-neoendorphin. See Reisine and Pasternak (1996).
Members of each known class of opioid receptor have been cloned from human cDNA and their predicted amino acid sequences have been determined. Yasuda et al. (1993) Proc. Natl. Acad. Sci. USA 90:6736; and Chen et al. (1993) Mol. Pharmacol. 44:8. The opioid receptors belong to a class of transmembrane spanning receptors known as G-protein coupled receptors. G-proteins consist of three tightly associated subunits, xcex1,xcex2and xcex3(1:1:1) in order of decreasing mass. Signal amplification results from the ability of a single receptor to activate many G-protein molecules, and from the stimulation by G-xcex1-GTP of many catalytic cycles of the effector. Most opioid receptor-mediated functions appear to be mediated through G-protein interactions. Standifer and Pasternak (1997) Cell Signal. 9:237. Antisense oligodeoxynucleotides directed against various G-protein xcex1 subunits were shown to differentially block the analgesic actions of the mu-, delta-, and kappa-opioid agonists in mice. Standifer et al. (1996) Mol. Pharmacol. 50:293.
Local anesthetics prevent or relieve pain by interrupting nerve conduction. When applied locally to nerve tissue in appropriate concentrations, local anesthetics reversibly block the action potentials responsible for nerve conduction. In general, their action is restricted to the site of application and rapidly reverses upon diffusion from the site of action in the nerve. The necessary practical advantage of the local anesthetics is that their action is reversible at clinically relevant concentrations; their use is followed by complete recovery in nerve function with no evidence of damage to nerve fibers or cells. For a detailed review of local anesthetics, see Catterall and Mackie (1996) Goodman and Gilman""s, The pharmacologic basis of therapeutics, Ninth Edition (Hardman et al. eds.) McGraw-Hill pp. 331-347; and Hanson (1995) Remington: The Science and Practice of Pharmacy, 17th edition, Mack Publishing Company pp. 1146-1153.
Local anesthetics can be administered by a variety of routes, including topical, infiltration, field or nerve block, intravenous regional, spinal, or epidural, as dictated by clinical circumstances. Local anesthetics act on any part of the nervous system and on every type of nerve fiber. Thus, a local anesthetic in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated. A wide variety of topical anesthetics are available. These include, but are not limited to, Benzocaine, cocaine, cocaine hydrochloride, Dibucaine, Dyclonine Hydrochloride, Lidocaine, Pramoxine Hydrochloride, Proparacaine Hydrochloride, Tetracaine, benoxinate, hydrochloride, butamben picrate, butamben oil, clove oil, eugenol and combinations thereof such as Benzocaine, Butamben and Tetracaine Hydrochloride; and Benzalkonium chloride and Lidocaine Hydrochloride. See, e.g., Remington (1995) for descriptions of the compositions and uses thereof. The salts and base forms of the esters and amides of these anesthetics produce topical anesthesia. The salts do not penetrate intact skin, but both forms penetrate abraded or raw granulated skin surfaces. The base forms relieve pruritus, burning and surface pain on intact skin, but penetrate only to a limited degree. Wounds, ulcers and burns are preferably treated with preparations relatively insoluble in tissue fluids.
Mucous membranes of the nose, mouth, pharynx, larynx, trachea, bronchi and urethra are anesthetized readily by both salt and base forms. Consequently, these agents are used prior to inserting intratracheal catheters, pharyngeal and nasal airways, nasogastric and endoscopic tubes, urinary catheters, laryngoscopes, proctoscopes, sigmoidoscopes and vaginal specula. Many of these agents are also used in the eye for such procedures as tonometry, gonioscopy and for removal of foreign bodies from the cornea or conjunctiva. Remington (1995).
Although a variety of physicochemical models have been proposed to explain how local anesthetics achieve conduction block, it is now generally accepted that the major mechanism of action of these drugs involves their interaction with one or more specific binding sites within the Na+ channel. For review, see Courtney and Strichartz (1987) Handbook of Experimental Pharmacology, Vol. 81. (Strichartz ed.) Springer-Verlag pp. 53-94. Local anesthetics prevent the generation and the conduction of nerve impulses through direct interaction with voltage-gated Na+ channels located in the cell membrane. They bind to a specific receptor site within the pore of the Na+ channel, blocking ion movement through this pore. This action decreases or prevents the large transient increase in the permeability of excitable membranes to Na+ that is normally produced by a slight depolarization of the membrane. As anesthetic action progressively develops in the nerve, the threshold for electrical excitability gradually increases, the rate of rise of the action potential declines, impulse conduction slows, and the safety factor for conduction decreases; these factors decrease the probability of propagation of the action potential, and nerve conduction fails.
The degree of block produced by a given concentration of local anesthetic depends on how the nerve has been stimulated and on its resting membrane potential. Thus, a resting nerve is much less sensitive to a local anesthetic than is one that is repetitively stimulated; higher frequency of stimulation and more positive membrane potential cause a greater degree of anesthetic block. Local anesthetic frequency- and voltage-dependent effects occur because the local anesthetic molecule, in its charged form, gains access to its binding site within the pore only when the Na+ channel is in an open state, as the local anesthetic binds more tightly to and stabilizes the inactivated state of the Na+ channel. Courtney and Strichartz (1987); and Butterworth and Strichartz (1990) Anesthesiol. 72:711. Generally, local anesthetic action frequency-dependence depends critically on the dissociation rate from the receptor site in the pore of the Na+ channel. A high stimulation frequency is required for rapidly dissociating drugs so that drug binding during the action potential exceeds dissociation between action potentials.
Biochemical, biophysical, and molecular biological investigations during the past decade have led to a rapid expansion of knowledge about the structure and function of the Na+ channel and other voltage-gated ion channels. Catterall (1992) Science 242:50. The Na+ channels of the mammalian brain are heterotrimeric complexes of glycosylated proteins with an aggregate molecular size in excess of 300 kDa; the individual subunits are designated xcex1(260 kDa),xcex21(36 kDa), and xcex22(33 kDa). The large xcex1 subunit of the Na+ channel contains four homologous domains (I to IV); each domain is thought to consist of six transmembrane domains or spans in xcex1-helical conformation. The Na+-selective transmembrane pore of the channel is presumed to reside in the center of a nearly symmetrical structure formed by the four homologous domains. The voltage-dependence of channel opening is hypothesized to reflect conformational changes that result from the movement of xe2x80x9cgating chargesxe2x80x9d (voltage sensors) in response to changes in the transmembrane potential.
The metabolic fate of local anesthetics is of great practical importance, because their toxicity depends largely on the balance between their rates of absorption and elimination. Since toxicity is related to the free concentration of drug, binding of the anesthetic to serum proteins and tissues reduces the concentration of free drug in systemic circulation and, consequently, reduces toxicity. In the case of topically applied local anesthetics, systemic absorption is so low that systemic toxicity is rarely an issue.
Lidocaine (XYLOCAINE), introduced in 1948, is now the most widely used local anesthetic. Lidocaine shares pharmacologic actions with other local anesthetic drugs. Lidocaine is an aminoethylamide and is the prototypical member of this class of local anesthetics. It is a good choice for individuals sensitive to ester-type local anesthetics.
The chemical and pharmacologic properties of each drug determine its clinical use. Lidocaine has a wide range of clinical uses as a local anesthetic; it has utility in almost any application where a local anesthetic of intermediate duration is needed. Lidocaine is also used as an antiarrhythmic agent. Lidocaine blocks both open and inactivated cardiac Na+ channels. Recovery from block is very rapid, so lidocaine exerts greater effects in depolarized (e.g., ischemic) and/or rapidly driven tissues.
Some local anesthetic agents are too toxic to be given by injection. Their use is restricted to topical application to the eye, the mucous membranes, or the skin. Many local anesthetics are suitable, however, for infiltration or injection to produce nerve block; some of them also are useful for topical application. Some anesthetics are either too irritating or too ineffective to be applied to the eye. However, they are useful as topical anesthetic agents on the skin and/or mucous membranes. These preparations are effective in the symptomatic relief of anal and genital pruritus, poison ivy rashes, and numerous other acute and chronic dermatoses. They are sometimes combined with a glucocorticoid or antihistamine and are available in a number of proprietary formulations.
Dibucaine (NUPECAINAL) is a quinoline derivative. Its toxicity resulted in its removal from the U.S. market as an injectable preparation; however, it is widely popular outside the U.S. as a spinal anesthetic and is currently available as a cream and an ointment for use on the skin.
Dyclonine hydrochloride (DYCLONE) has rapid onset of action and duration of effect comparable to procaine. It is absorbed through the skin and mucous membranes. The compound is used as 0.5% or 1.0% solution for topical anesthesia during endoscopy, for oral mucositis pain following radiation or chemotherapy, and for anogenital procedures.
Pramoxine hydrochloride (ANUSOL, TRONOTHANE, others) is a surface anesthetic agent that is not a benzoate ester. Its distinct chemical structure can help minimize the danger of cross-sensitivity reactions in patients allergic to other local anesthetics. Pramoxine produces satisfactory surface anesthesia and is reasonably well tolerated on the skin and mucous membranes. It is usually too irritating to be used on the eye or in the nose. Various preparations are available for topical application, usually including 1% pramoxine.
Some local anesthetics are poorly soluble in water and, consequently, too slowly absorbed to be toxic. They can be applied directly to wounds and ulcerated surfaces, where they remain localized for long periods of time to produce a sustained anesthetic action. Chemically, they are esters of paraaminobenzoic acid which lack the terminal amino group of the previously described local anesthetics. The most important member of this series is benzocaine (ethyl aminobenzoate or AMERICAINE ANESTHETIC). Benzocaine is structurally similar to procaine, differing by the lack of a terminal diethylamino group. It is incorporated into a large number of topical preparations. Benzocaine has been reported to cause methemoglobinemia; dosing recommendations must be carefully followed.
Anesthesia of the cornea and conjuctiva can be obtained readily by topical application of local anesthetics. However, most of the local anesthetics described above can be irritating when administered for ophthalmologic use. The two compounds most frequently used are proparacaine (ALCAINE, OPHTHAINE, others) and tetracaine. Proparacaine has the advantage of bearing little antigenic similarity to the other benzoate local anesthetics and therefore, can be used in individuals sensitive to the amino ester local anesthetics.
For use in ophthalmology, suitable local anesthetics are instilled a single drop at a time. If anesthesia is incomplete, successive drops are applied until satisfactory conditions are obtained. The duration of anesthesia is determined chiefly by the vascularity of the tissue; thus anesthesia is longest in normal cornea and least in inflamed conjunctiva. In the latter, repeated instillations are necessary to maintain adequate anesthesia for the duration of the procedure. Long-term administration of topical anesthesia to the eye causes retarded healing and pitting, sloughing of the corneal epithelium and predisposition of the eye to inadvertent injury. Thus, these drugs are not usually prescribed for self-administration.
Topical administration of pain-relieving drugs to the periphery offers important advantages over systemic or local, non-topical administration. For example, topical administration of opioids decreases side effects, such as sedation, respiratory depression and nausea. Even transdermal administration of opioids can elicit systemic responses and thus, produce unwanted side effects. See U.S. Pat. Nos. 5,686,112; and 4,626,539. Benefits associated with topical administration of opioid analgesic drugs are discussed in U.S. Pat. Nos. 5,589,480; 5,866,143; and 5,834,480. Even further, limiting drug delivery to the actual site of administration can eliminate peripheral side effects such as constipation.
Topically administered morphine activity has been measured by the radiant heat tailflick assay in mice. Kolesnikov and Pasternak (1999) J. Pharmacol. Exp. Ther. 290:247. This assay, determined that analgesia provided by topical morphine is restricted to tail regions exposed to the drug. Opioids acting through kappa and delta receptors also exhibit peripheral activity. Kolesnikov and Pasternak (1999); and Kolesnikov et al. (1996) Eur. J. Pharmacol. 310:141. It has been shown that NMDA antagonists block opioid tolerance when applied topically. Kolesnikov and Pasternak (1999). Topical administration of NMDA antagonists to the periphery circumvents the undesirable side effects that preclude systemic use. Utilization of topical drug delivery allows for the combined use of opioids and NMDA antagonists.
Opioids are known to work in combination with other classes of drugs. See U.S. Pat. Nos. 5,840,731; and 5,869,498; and WO 97/10815. Synergistic potentiation of opioid-induced analgesia is the most highly desirable effect for the clinical management of pain. This phenomenon was first observed between supraspinal and spinal sites (Yeung and Rudy (1980) J. Pharmacol. Exp. Ther. 215:633), and has since been observed between brainstem nuclei (Rossi et al. (1993) Brain Res. 665:85), as well as between peripheral and central sites (Kolesnikov et al. (1996) J. Pharmacol. Exp. Ther. 279:247). Synergy occurs between opioids of different classes. Adams et al. (1993) J. Pharmacol. Exp. Ther. 266:1261; He and Lee (1998) J. Pharmacol. Exp. Ther. 285:1181; Horan et al. (1992) Life Sci. 50:1535; and Rossi et al. (1994) Brain Res. 665:85. Clinical studies have shown that the systemic administration of lidocaine and opioids effectively reduces pain. Atanassoff et al. (1997) Anesth. Analg. 84:1340; Saito et al. (1998) Anesthesiol. 89:1455; and Saito et al. (1998) Anesthesiol. 89:1464. Currently, pharmacologic relationships between these two classes of drugs are not well characterized.
The invention encompasses pharmaceutical compositions comprising at least two compounds, at least one effecting opioid analgesia and at least one effecting local anesthesia, in amounts sufficient to potentiate an antinociceptive response when both compounds are topically administered in a physiologically acceptable topical excipient.
The invention further encompasses a method of providing topical analgesia to a subject comprising topical administration of a pharmaceutical composition comprising at least two compounds, at least one effecting opioid analgesia and at least one effecting local anesthesia, wherein the pharmaceutical composition is administered in a physiologically acceptable topical excipient and in an amount and a duration sufficient to potentiate an antinociceptive response.